1. Field of the Invention
The invention relates to a process, and the intermediates useful in such a process, for the preparation of decahydroisoquino[2,1-g][1,6]naphthyridin-8-one derivatives as single enantiomers, and chiral acid addition salts thereof. The invention also relates to the use of such derivatives for a preferred preparation of decahydro-8H-isoquino[2,1-g][1,6]naphthyridine compounds as single enantiomers, examples of which are disclosed in U.S. Pat. Nos. 4,791,108, 4,886,798 and 4,956,365. The exemplified decahydro-8H-isoquino[2,1-g][1,6]naphthyridine compounds exhibit selective .alpha..sub.2 -blockade in mammals, and are therefore useful as medicaments for the treatment of physiological conditions affected by such selective blockade.
2. Previous Disclosures
Processes for the preparation of compounds of formula (I), as single enantiomers or as a mixture of enantiomers, are disclosed in U.S. patent application Ser. No. 336,993, and in U.S. Pat. Nos. 4,791,108, 4,886,798 and 4,956,365, the disclosures of which are hereby incorporated by reference.
The present process provides for an improved preparation of single enantiomers represented by the formula (I), i.e. the (8aS,12aS,13aS) enantiomer, and chiral acid addition salts thereof represented by the formula (IA) (as shown in the Summary of the Invention). The invention provides most particularly a process for the large-scale production of (I) and (IA). The process has surprising advantages over previously disclosed processes in that it does not require the use of low temperatures (some steps of previous processes were carried out at -78.degree. C.), does not require expensive nicotinic acid derivatives as starting materials, requires no unwieldy and time-consuming chromatographic separations, does not require isolation of intermediates at each step (and those intermediates that are separated are highly crystalline, thus simplifying the separation procedure), and the hydrogenation step may be adapted to be carried out at either high or low pressure. In addition, the resolution step surprisingly provides for a highly efficient separation of a single enantiomer from a mixture of diastereoisomers, in contrast to conventional procedures that require multiple crystallizations to separate the isomers from a single racemic compound.